Cleft Laterality Dental Arch Relationship Outcomes for Children with Unilateral Cleft Lip and Palate in New Zealand.

OBJECTIVES: To investigate cleft laterality dental arch relationship outcomes of children with non-syndromic complete unilateral cleft lip and palate (UCLP) in New Zealand. DESIGN: A retrospective nationwide study. SETTINGS: Virtual 3D orthodontic study models collected prior to undertaking secondary alveolar bone grafting. PARTICIPANTS: A total of 104 patients with UCLP (L = 80: R = 24). OUTCOME MEASURES: Four calibrated assessors used the GOSLON Yardstick and 100 mm Visual Analogue Scale (VAS) to score the randomised models on 2 separate assessment sessions. Weighted Kappa were used to determine the intra/inter-rater reliability for the GOSLON and correlations for the VAS. RESULTS: Intra-rater reliability ranged from 0.57-0.88 (GOSLON) and 0.45-0.93 (VAS). Inter-rater reliability ranged from 0.62-0.86 (GOSLON) and 0.64-0.93 (VAS).GOSLON scores for the left UCLP were 31.2% for good/very good; 26.3% for fair; 42.5% for poor/very poor while the right UCLP scored 8.3% for good/very good; 37.5% for fair; 54.2% for poor/very poor. The mean VAS for left and right UCLP were 53.4 (sd 22.5) and 44.6 (sd 17.1) respectively. Neither the GOSLON nor VAS differences reached statistical significance (both P = .08). CONCLUSIONS: From a clinical perspective right UCLP had worse dental arch relationship outcomes, however, these differences failed to reach statistical significance. Further studies using larger sample sizes are required to determine if cleft laterality is an important consideration when investigating UCLP dental arch outcomes.

Prevalence of urinary tract infection and antimicrobial resistance patterns of uropathogens with biofilm forming capacity among outpatients in morogoro, Tanzania: a cross-sectional study.

INTRODUCTION: Urinary tract infection (UTI) is the second most common infectious disease affecting more than 150 million people globally annually. Uropathogenic E. coli (UPEC), the predominant cause of UTI, can occur as a biofilm associated with antimicrobial resistance (AMR). There is a data gap on global AMR patterns from low-income settings, including Tanzania. Data on antimicrobial susceptibility patterns in relation to biofilm formation will help in the proper selection of antibiotics and the fight against AMR. METHODS: This analytical cross-sectional study was conducted among consecutively selected outpatients (n = 344) from January to May 2022 at Morogoro Regional Referal Hospital. Mid-stream urine samples were collected aseptically from symptomatic patients. A significant UTI was defined when more than 105 colonies/ml of urine were recorded. Kirby Bauer's disc diffusion method was used for antibiotics susceptibility patterns and a Congo Red Agar method was used to determine biofilm formation. Two-sided χ2 test or Fisher's exact test, Cohen's kappa coefficient and logistic regression were used for data analysis. A p-value < 0.05 was considered statistically significant. RESULTS: The prevalence of UTIs was 41% (141/344) and elders (>=60 years) had five times higher odds of having UTI as compared to adolescents (p < 0.001). E. coli was the most predominant bacteria (47%; 66/141), which displayed moderate susceptibility against ciprofloxacin (59.1%) and nitrofurantoin (57.6%). A total of 72 (51%) of all isolated bacteria were multi-drug resistant. All isolated bacteria demonstrated high resistance (> 85%) against ampicillin and co-trimoxazole. In this study, 51.5% (34/66) were biofilm-forming E. coli and demonstrated relatively higher antibiotic resistance as compared to non-biofilm forming bacteria (p < 0.05). CONCLUSION: We report high antibiotic resistance against commonly used antibiotics. Slightly more than half of the isolated bacteria were biofilm forming E. coli. A need to strengthen stewardship programs is urgently advocated.

Characterizing the role of Phlda3 in the development of acute toxicity and malignant transformation of hematopoietic cells induced by total-body irradiation in mice.

The tumor suppressor p53 is a transcriptional factor that plays a crucial role in controlling acute toxicity and long-term malignant transformation of hematopoietic cells induced by genotoxic stress such as ionizing radiation. Among all transcriptional targets of p53, one gene that is robustly induced by radiation is the pleckstrin homology domain-only protein Phlda3. However, the role that Phlda3 plays in regulating the response of hematopoietic cells to radiation is unknown. Here, using isogenic cell lines and genetically engineered mouse models, we showed that radiation induces Phlda3 in human leukemia cells and mouse normal hematopoietic cells in a p53-dependent manner. However, deletion of the Phlda3 gene did not ameliorate radiation-induced acute hematologic toxicity. In addition, distinct from mice that lose p53, loss of Phlda3 did not alter the latency and incidence of radiation-induced thymic lymphoma in mice. Remarkably, whole-exome sequencing data showed that lymphomas in irradiated Phlda3+/+ mice harbor a significantly higher number of single nucleotide variants (SNVs) and indels compared to lymphomas in irradiated Phlda3+/- and Phlda3-/- littermates. Together, our results indicate that although deletion of Phlda3 does not accelerate the development of radiation-induced thymic lymphoma, fewer SNVs and indels are necessary to initiate lymphomagenesis after radiation exposure when Phlda3 is silenced.

The demographic history of house mice (Mus musculus domesticus) in eastern North America.

The Western European house mouse (Mus musculus domesticus) is a widespread human commensal that has recently been introduced to North America. Its introduction to the Americas is thought to have resulted from the transatlantic movements of Europeans that began in the early 16th century. To study the details of this colonization history, we examine population structure, explore relevant demographic models, and infer the timing of divergence among house mouse populations in the eastern United States using published exome sequences from five North American populations and two European populations. For North American populations of house mice, levels of nucleotide variation were lower, and low-frequency alleles were less common than for European populations. These patterns provide evidence of a mild bottleneck associated with the movement of house mice into North America. Several analyses revealed that one North American population is genetically admixed, which indicates at least two source populations from Europe were independently introduced to eastern North America. Estimated divergence times between North American and German populations ranged between ∼1,000 and 7,000 years ago and overlapped with the estimated divergence time between populations from Germany and France. Demographic models comparing different North American populations revealed that these populations diverged from each other mostly within the last 500 years, consistent with the timing of the arrival of Western European settlers to North America. Together, these results support a recent introduction of Western European house mice to eastern North America, highlighting the effects of human migration and colonization on the spread of an invasive human commensal.

The role of neutrophil to lymphocyte ratio in predicting lung metastasis in giant cell tumor of the extremities.

OBJECTIVE: Inflammation has a vital role in tumor development and metastasis. Changes in blood count parameters have been associated with tumor prognosis. We aimed to evaluate the prognostic significance of neutrophil to lymphocyte ratio (NLR) in predicting lung metastasis of giant cell tumors of the bone (GCTB) of the extremities. PATIENTS AND METHODS: 34 GCTB patients (22 males and 12 females) were included in the study. Patients were divided into two groups. The metastasis group (n = 7) included GCTB patients with lung metastasis, while the non-metastasis group (n = 27) included those without lung metastasis. Descriptive statistics and frequency distribution were calculated [age, white blood cell (WBC), neutrophil, lymphocyte, platelets, neutrophil to lymphocyte ratio (NLR), and platelets to lymphocytes ratio (PLR)]. Continuous normal variables were expressed as mean ± standard deviation and compared using Student's t-tests. The receiver operating characteristic (ROC) curve analysis was used to evaluate the ability of NLR and PLR to predict lung metastasis. The factors were considered to be statistically significant at p < 0.05. RESULTS: There were no significant differences between the lymphocyte count (1.81 vs. 2.23 103/mm3), platelet count (436 vs. 364 103/mm3), and PLR values (247 vs. 190) of the two groups (p > 0.05). The WBC count (11.8 vs. 8.95 103/mm3), neutrophil count (8.78 vs. 5.69 103/mm3), and NLR levels (5.45 vs. 2.81) (p < 0.05) were significantly higher in the metastasis group. The presence of an NLR cut-off value of 3.7 significantly predicted the existence of lung metastasis (AUC = 0.857 [95%CI = 0.714-1], p = 0.004) with a sensitivity of 85% and specificity of 82%. CONCLUSIONS: NLR may serve as a promising prognostic marker for predicting lung metastasis in GCTB patients.

A proposed methodology for uncertainty extraction and verification in priority setting partnerships with the James Lind Alliance: an example from the Common Conditions Affecting the Hand and Wrist Priority Setting Partnership.

BACKGROUND: To report our recommended methodology for extracting and then confirming research uncertainties - areas where research has failed to answer a research question - derived from previously published literature during a broad scope Priority Setting Partnership (PSP) with the James Lind Alliance (JLA). METHODS: This process was completed in the UK as part of the PSP for "Common Conditions Affecting the Hand and Wrist", comprising of health professionals, patients and carers and reports the data (uncertainty) extraction phase of this. The PSP followed the robust methodology dictated by the JLA and sought to identify knowledge gaps, termed "uncertainties" by the JLA. Published Cochrane Systematic Reviews, Guidelines and Protocols, NICE (National Institute for Health and Care Excellence) Guidelines, and SIGN (Scottish Intercollegiate Guidelines Network) Guidelines were screened for documented "uncertainties". A robust method of screening, internally verifying and then checking uncertainties was adopted. This included independent screening and data extraction by multiple researchers and use of a PRISMA flowchart, alongside steering group consensus processes. Selection of research uncertainties was guided by the scope of the Common Conditions Affecting the Hand and Wrist PSP which focused on "common" hand conditions routinely treated by hand specialists, including hand surgeons and hand therapists limited to identifying questions concerning the results of intervention, and not the basic science or epidemiology behind disease. RESULTS: Of the 2358 records identified (after removal of duplicates) which entered the screening process, 186 records were presented to the PSP steering group for eligibility assessment; 79 were deemed within scope and included for the purpose of research uncertainty extraction (45 full Cochrane Reviews, 18 Cochrane Review protocols, 16 Guidelines). These yielded 89 research uncertainties, which were compared to the stakeholder survey, and added to the longlist where necessary; before derived uncertainties were checked against non-Cochrane published systematic reviews. CONCLUSIONS: In carrying out this work, beyond reporting on output of the Common Conditions Affecting the Hand and Wrist PSP, we detail the methodology and processes we hope can inform and facilitate the work of future PSPs and other evidence reviews, especially those with a broader scope beyond a single disease or condition.

Magnitude of Extended-Spectrum Beta-Lactamase-Producing Gram-Negative and Beta-Lactamase-Producing Gram-Positive Pathogens Isolated from Patients in Dar es Salaam, Tanzania: A Cross-Sectional Study.

Background The worldwide emergence of antibiotic-resistant bacteria threatens to overshadow the dramatic advances in medical sciences since the discovery of antibiotics. Antibiotic resistance has rendered some antibiotics obsolete, creating a reliance on synthetic drugs. In some instances, bacteria can be resistant to all antibiotics. The problem of antibiotic resistance is eminent in resource-limited countries like Tanzania, where systematic surveillance and routine susceptibility tests are rarely conducted. Therefore, this study aimed to investigate the magnitude of beta-lactamase-producing Gram-positive pathogens and Enterobacteriaceae with extended-spectrum beta-lactamase (ESBL) in Dar es Salaam, Tanzania. Methodology This multi-site cross-sectional study involved three private hospitals in Dar es Salaam, Tanzania. The study was conducted between July and September 2008. Bacterial isolates were collected, identified, and subjected to antibiotic-sensitivity testing against cephalosporins, including ceftriaxone, cefuroxime and cefotaxime, and clavulanic acid, which are antibiotics readily available on the Tanzanian market at the time of the study. The microdilution method was employed to determine beta-lactamase and ESBL production per the Clinical Laboratory and Standards Institute (CLSI) protocol. Cephalosporins, including ceftriaxone, cefuroxime and cefotaxime, the beta-lactamase inhibitor, and clavulanic acid, were serially diluted with concentrations ranging from 0.011 mg/ml to 200 mg/ml. Each of these antibiotics was subjected to sensitivity tests by determining the minimum inhibitory concentrations (MIC) of the clinical isolates of bacteria using a 96-well microdilution plate. Five microliters of bacterial suspension were inoculated into each well-containing 120µl of sterile Mueller-Hinton broth before incubation overnight. Results A total of 111 bacterial isolates were tested. Of the 111 tested bacterial isolates, 85 (76.6%) and 26 (23.4%) were Gram-negative and Gram-positive bacteria, respectively. Fifty-six clinical isolates (50.4%) were Escherichia coli, and 13 Salmonella species (11.7%) were among the Gram-negative isolates. On the other hand, 15 (13.5%) and 11 (9.9%) Gram-positive bacteria were Staphylococcus aureus and Streptococcus species, respectively, of all isolates. The majority of these clinical isolates, 71 (64.0%), were obtained from mid-stream urine, while the remaining were from stool, vaginal secretions, blood, pus, catheter sip, and urethra. A high proportion of tested Gram-negative bacteria, 58 (68.2%), were identified as ESBL producers, and 16 (61.5%) of the Gram-positive bacteria were identified as beta-lactamase producers. Cefuroxime was the least effective, exhibiting the largest MIC (18.47 ± 22.6 mg/ml) compared to clavulanic acid alone (5.28 ± 8.0 mg/ml) and clavulanic acid-cefuroxime (5.0± 12.32 mg/ml). Of all isolates, 78.2% were sensitive to chloramphenicol. Only five isolates had MIC larger than 32.23 mg/ml as opposed to cefotaxime and ampicillin, which had more isolates in that similar MIC range. Conclusion There is a high proportion of beta-lactamase, particularly ESBL-producing pathogens, in Dar es Salaam, Tanzania. Therefore, regular detection of beta-lactamase and ESBL production may help detect resistance to beta-lactam antibiotics.

Electromyographic differences of the gluteus maximus, gluteus medius, biceps femoris, and vastus lateralis between the barbell hip thrust and barbell glute bridge.

Hip extensor muscles are critical to sport performance as events requiring sprinting and forceful landings are highly dependent on these muscles. Despite biomechanical differences between the barbell hip thrust (BHT) and the barbell glute bridge (BGB), both are biomechanically efficient ways to load this musculature for training purposes. Research investigating the differences in muscular activity between the BHT and BGB has yet been conducted. The aim of this study was to investigate, through surface electromyography, if one exercise is more optimal than the other in producing greater muscle activation for specific hip extensor muscles. Ten male participants completed a two-part study protocol. Results revealed the BHT elicited significantly greater muscle activity within the vastus lateralis for peak and mean outcomes; however, the BGB elicited significantly greater muscle activity in the upper and lower gluteus maximus for peak and mean outcomes and mean outcome in the gluteus medius. Current findings suggest, the BGB is, at minimum, a superior substitute for the BHT for eliciting a larger magnitude of activity in the gluteus maximus. Future studies between the two exercises are warranted to discern which produces greater hypertrophy and whether adaption of the BHT or BGB transfers more optimally to sport performance.

Isolation Frequency of Fluconazole-Resistant Candida Species From Cockroaches: A Cross-Sectional Study From a National Hospital in Dar es Salaam, Tanzania.

BACKGROUND: Cockroaches are common pests in homes and hospitals. They cause allergic reactions in some individuals and are potential vectors for various infectious pathogens. The study investigated the extent to which hospital cockroaches act as vectors and reservoirs of medically important fungal pathogens on their external surfaces. METHODS: Cockroaches were captured from the selected hospital locations including the burn unit, adult surgical wards, pediatric oncology wards, intern hostel kitchen, and the central kitchen of a national referral teaching hospital in Tanzania. Normal saline washings from the external surface of cockroaches were cultured on standard mycological media to facilitate isolation and identification of medically important molds and yeasts. The susceptibility of Candida species isolates to fluconazole was tested using the Clinical and Laboratory Standards Institute (CLSI) M27-A3 microdilution method. RESULTS: A total of 69 cockroaches were captured from various hospital sites between February and April 2017. All cockroaches captured were shown to carry medically important fungi. A total of 956 medically important fungi were isolated; 554 (57.9%) were of Candida species, 222 (23.2%) were of Aspergillus species, 30 (3.1%) were of​​​​​​​ Cladosporium species, 17 (1.8%) were of​​​​​​​ Rhizopus species, 11 (1.2%) were of​​​​​​​ Geotrichum species, nine (0.9%) were of​​​​​​​ Penicillium species, seven (0.7%) were of​​​​​​​ Alternaria species, six (0.6%) were of​​​​​​​ Fusarium species, three (0.3%) were of​​​​​​​ Mucor species, and 97 (10.1%) were of other species. Of the Aspergillus species, Aspergillus fumigatus (111, 50.0%) was the most commonly isolated, followed by Aspergillus niger (35, 15.8%) among the Aspergillus isolates. Out of the 103 selected isolates, 18 (17.5%) of the Candida isolates normally not intrinsically resistant to fluconazole demonstrated resistance to this drug. Resistance was most frequently found in Candida parapsilosis (3, 30%), Candida pseudotropicalis (10, 23.8%), and Candida glabrata (2, 18.2%). The isolates with the least proportion of resistance to fluconazole were Candida albicans (2, 6.3%). CONCLUSION: Cockroaches from this hospital may act as reservoirs of medically important opportunistic fungi exhibiting resistance to fluconazole.

Transcranial Infrared Laser Stimulation for the Treatment of Traumatic Brain Injury: A Case Series.

Introduction: This study intended to evaluate the safety and possible therapeutic effect of transcranial infrared laser stimulation (TILS) based on photobiomodulation (PBM) among patients with traumatic brain injury (TBI). Methods: Eleven participants who were diagnosed with TBI after full neurological examination and MRI evaluation by a board-certified neurologist completed five to eight 20-minute TILS sessions using the Cytonsys CytonPro-5000 apparatus (pilot laser control, focused wavelength of 1064 nm, maximum output power of 10W, maximum optical power density of 500 mW/cm2, effective area 4.5 cm2 in diameter). Per TILS session, participants underwent a laser dose of 250 mW/cm2 continuous laser wave to each hemisphere using predetermined patient-specific coordinates. Structural imaging was used to neuronavigate individual treatment targets in the frontal cortex (Brodmann area 10). The primary safety measure for this study was the occurrence of adverse events (AEs) or serious adverse events (SAEs). The primary efficacy outcome measure was the participant-rated global rating of change (GRC) post-intervention. Secondary outcome measures included a battery of neuropsychological testing and mood questionnaires done both pre- and post-intervention. Results: All patients enrolled in this study protocol were able to tolerate the study procedures without any AEs or SAEs. Nine out of eleven participants had clinically significant improvements in GRC score (≥ +2). Neuropsychological testing and mood questionnaire outcomes also suggested a positive therapeutic effect. Conclusion: This study provides preliminary evidence supporting the safety and potential efficacy of TILS as a non-invasive clinical intervention for individuals with TBI.

Treatment of Dementia With Bosutinib: An Open-Label Study of a Tyrosine Kinase Inhibitor.

OBJECTIVE: The pursuit of an effective therapeutic intervention for dementia has inspired interest in the class of medications known as tyrosine kinase inhibitors such as bosutinib. METHODS: Thirty-one patients with probable Alzheimer dementia or Parkinson spectrum disorder with dementia completed 12 months of bosutinib therapy and an additional 12 months of follow-up. The Clinical Dementia Rating scale (as estimated by the Quick Dementia Rating System [QDRS]) was the primary cognitive status outcome measure. Secondary outcome measures included the Repeatable Battery Assessment of Neuropsychological Status (RBANS) and the Montreal Cognitive Assessment. Cox regression methods were used to compare results with population-based estimates of cognitive decline. RESULTS: The present article reports on cognitive outcomes obtained at 12 months for 31 participants and up to 24 months for a 16-participant subset. Safety and tolerability of bosutinib were confirmed among the study population (Mage = 73.7 years, SDage = 14 years). Bosutinib was associated with less worsening in Clinical Dementia Rating (CDR) scores (hazard ratio = -0.62, p < 0.001, 95% confidence interval [CI]: -1.02 to -0.30) and less decline in RBANS performance (hazard ratio = -3.42, p < 0.001, 95% CI: -3.59 to -3.72) during the year of treatment than population-based estimates of decline. In the 24-month follow-up, wherein 16 patients were observed after 1 year postintervention, 31.2% of participants exhibited worsened CDR levels compared with their 12-month performances. CONCLUSIONS: Results support an overall positive outcome after 1 year of bosutinib. Future studies should explore the relationship between tyrosine kinases and neurodegenerative pathology as well as related avenues of treatment.

Translating state-of-the-art brain magnetic resonance imaging (MRI) techniques into clinical practice: multimodal MRI differentiates dementia subtypes in a traditional clinical setting.

BACKGROUND: This study sought to validate the clinical utility of multimodal magnetic resonance imaging (MRI) techniques in the assessment of neurodegenerative disorders. We intended to demonstrate that advanced neuroimaging techniques commonly used in research can effectively be employed in clinical practice to accurately differentiate heathy aging and dementia subtypes. METHODS: Twenty patients with dementia of the Alzheimer's type (DAT) and 18 patients with Parkinson's disease dementia (PDD) were identified using gold-standard techniques. Twenty-three healthy, age and sex matched control participants were also recruited. All participants underwent multimodal MRI including T1 structural, diffusion tensor imaging (DTI), arterial spin labeling (ASL), and magnetic resonance spectroscopy (MRS). MRI modalities were evaluated by trained neuroimaging readers and were separately assessed using cross-validated, iterative discriminant function analyses with subsequent feature reduction techniques. In this way, each modality was evaluated for its ability to differentiate patients with dementia from healthy controls as well as to differentiate dementia subtypes. RESULTS: Following individual and group feature reduction, each of the multimodal MRI metrics except MRS successfully differentiated healthy aging from dementia and also demonstrated distinct dementia subtypes. Using the following ten metrics, excellent separation (95.5% accuracy, 92.3% sensitivity; 100.0% specificity) was achieved between healthy aging and neurodegenerative conditions: volume of the left frontal pole, left occipital pole, right posterior superior temporal gyrus, left posterior cingulate gyrus, right planum temporale; perfusion of the left hippocampus and left occipital lobe; fractional anisotropy (FA) of the forceps major and bilateral anterior thalamic radiation. Using volume of the left frontal pole, right posterior superior temporal gyrus, left posterior cingulate gyrus, perfusion of the left hippocampus and left occipital lobe; FA of the forceps major and bilateral anterior thalamic radiation, neurodegenerative subtypes were accurately differentiated as well (87.8% accuracy, 95.2% sensitivity; 85.0% specificity). CONCLUSIONS: Regional volumetrics, DTI metrics, and ASL successfully differentiated dementia patients from controls with sufficient sensitivity to differentiate dementia subtypes. Similarly, feature reduction results suggest that advanced analyses can meaningfully identify brain regions with the most positive predictive value and discriminant validity. Together, these advanced neuroimaging techniques can contribute significantly to diagnosis and treatment planning for individual patients.

Rare and Complicated Overlap of Stevens-Johnson Syndrome and Acute Generalized Exanthematous Pustulosis.

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and acute generalized exanthematous pustulosis (AGEP) are two separate pathological entities of severe cutaneous adverse reactions (SCARs) with different etiologies and treatment strategies. Diagnosis is, however, complicated by the similarity in their clinical presentation. Although there are few claims of AGEP-SJS/TEN overlap, a simultaneous true overlap of SJS/TEN and AGEP has rarely been described in the literature. Here, we report a case study of a 61-year-old female with a known allergy to sulfa drugs presenting with altered mental status, generalized weakness, and erythematous and excoriated purulent wounds. Based on initial workup and extensive consultation, the patient was diagnosed with severe sepsis secondary to diffuse purulent cellulitis, community-acquired pneumonia, and acute renal failure due to prerenal azotemia from dehydration. She was treated with several antibiotics, starting with vancomycin, piperacillin/tazobactam. Six days later, antibiotics were de-escalated to ceftriaxone and metronidazole because of the patient's improved status. The medications were withheld when the patient started developing extensive blistering on day 8. Blood cultures ruled out any bacterial etiology. Skin biopsy confirmed overlapping features of AGEP and SJS/TEN. Due to the uncontrolled progression of her rash, she was transferred to the burn unit of a higher care center. This is potentially the first histologically confirmed case of AGEP-SJS/TEN overlap in the United States. In this case study, a conclusive diagnosis would have never been made without a biopsy, especially because the condition presented clinically as SJS/TEN. We, therefore, recommend considering a potential overlap of multiple pathologies at each presentation or suspicion of a SCAR and performing an early skin biopsy in order to provide definitive diagnosis and treatment.

Whole-Exome Sequencing of Radiation-Induced Thymic Lymphoma in Mouse Models Identifies Notch1 Activation as a Driver of p53 Wild-Type Lymphoma.

Mouse models of radiation-induced thymic lymphoma are widely used to study the development of radiation-induced blood cancers and to gain insights into the biology of human T-cell lymphoblastic leukemia/lymphoma. Here we aimed to identify key oncogenic drivers for the development of radiation-induced thymic lymphoma by performing whole-exome sequencing using tumors and paired normal tissues from mice with and without irradiation. Thymic lymphomas from irradiated wild-type (WT), p53+/-, and KrasLA1 mice were not observed to harbor significantly higher numbers of nonsynonymous somatic mutations compared with thymic lymphomas from unirradiated p53-/- mice. However, distinct patterns of recurrent mutations arose in genes that control the Notch1 signaling pathway based on the mutational status of p53. Preferential activation of Notch1 signaling in p53 WT lymphomas was also observed at the RNA and protein level. Reporter mice for activation of Notch1 signaling revealed that total-body irradiation (TBI) enriched Notch1hi CD44+ thymocytes that could propagate in vivo after thymocyte transplantation. Mechanistically, genetic inhibition of Notch1 signaling in immature thymocytes prevented formation of radiation-induced thymic lymphoma in p53 WT mice. Taken together, these results demonstrate a critical role of activated Notch1 signaling in driving multistep carcinogenesis of thymic lymphoma following TBI in p53 WT mice. SIGNIFICANCE: These findings reveal the mutational landscape and key drivers in murine radiation-induced thymic lymphoma, a classic animal model that has been used to study radiation carcinogenesis for over 70 years.

Cytotoxicity of a new tirucallane derivative isolated from Stereospermum acuminatissimum K. Schum stem bark.

One new tirucallan derivative, leutcharic acid (1) was isolated from Stereospermum acuminatissimum stem bark together with the known compounds 3-oxo-22-hydroxyhopane (2), 3,4-secotirucalla-4(28),7,24-trien-3,21-dioic acid (3), 3-oxotirucalla-7,24-dien-21-oic acid (7), lupeol (4), ß-sitosterol (5) and stigmasterol (6). The structures of the isolated compounds were elucidated using 1 D and 2 D NMR spectroscopy in combination with literature data. To the best of our knowledge, this is the first report on the cytotoxic properties' constituents of S. acuminatissimum. Cytotoxicity of compounds 1 and 2 was assessed in vitro with the WST-1 assay on human lung adenocarcinoma A549 and THP-1 human monocytic leukaemia cell lines. Both compounds showed antiproliferative activity on the cancer cells. Compound 2 was more active against THP-1 with an IC50 value of 26.83 µM. The sensitivity of THP-1 cells to compounds 1 and 2 indicated that these compounds might be potential leads for anticancer agent development against leukaemia.

Investigation of Johne's disease in Tasmanian fallow deer (Dama dama).

In 2012 when many sheep flocks in northern-central Tasmania were experiencing a high prevalence of ovine Johne's disease, 34 wild adult fallow deer shot on or near infected properties were negative to microscopic Mptb lesions of the ileo-caecal valve, terminal ileum and ileo-caecal lymph nodes. This study demonstrated 95% confidence of detecting Johne's disease in this fallow deer population if ≥10% of animals were shedding Mycobacterium avium subsp. paratuberculosis in their faeces, or if ≥21% of animals were sub-clinically infected.

Assessment of Implementation of Antimicrobial Resistance Surveillance and Antimicrobial Stewardship Programs in Tanzanian Health Facilities a Year After Launch of the National Action Plan.

Introduction: Antimicrobial resistance (AMR) is a current global health threat and a challenge to the treatment of infectious diseases. The WHO advocates a strategy of antibiotic stewardship programs (ASP) in optimizing antimicrobial use in hospitals. This study aimed at assessing the existence of AMR surveillance and ASP implementation in health facilities in Tanzania in the year following the launch of the National Action Plan (NAP). Methodology: From December 2017 through July 2018, a descriptive cross-sectional study was conducted using a structured questionnaire administered online. A total of 199 health facilities in Tanzania mainland whose contacts was obtained from the Ministry of Health Community Development Gender Elderly and Children (MoHCDGEC) were reached by phone and thereafter, a survey was sent via text or e-mail to focal persons in the corresponding facilities. Results: Only 39 (32.5%) responses from contacted facilities were received and analyzed. Thirty (76.9%) of the facilities were government-owned. Of the 39 respondents surveyed, 13 (35.9%) declared to have implemented some sort of coordinated ASP to promote the rational use of antimicrobials at their facilities. The respondents reported the presence of guidelines for the implementation of ASP at variable proportions, whereas the presence of a committee for Infection Prevention and Control was reported by 27 (69.2%). Twenty-four (61.5%) had a Medical and Therapeutic Committee. Although all 39 (100%) respondents were aware of the presence of AMR in Tanzania, only 26 (66.7%) were aware of the presence of the Tanzanian NAP for AMR. Hospital antibiotic policy document was present in 6 (15.4%) facilities. Only 7 (17.9%) facilities conducted prescription auditing; 9 (23.1%) had a hospital formulary; 14 (35.9%) had standard hospital prescription. 9 (23.1%) had software for data storage about AMR. Only 7 (17.9%) facilities conducted microorganisms' susceptibility tests and kept the record of the microorganism susceptibility testing. Conclusion: Our study found the existence of AMR surveillance activities and ASP implementation in Tanzania, albeit at a low level. The implementation was inconsistent across the surveyed facilities. These data have identified areas of improvement in addressing AMR in Tanzania through the NAP.

The Existence of High Bacterial Resistance to Some Reserved Antibiotics in Tertiary Hospitals in Tanzania: A Call to Revisit Their Use.

BACKGROUND: Antibiotic resistance poses burden to the community and health-care services. Efforts are being made at local, national and global level to combat the rise of antibiotic resistance including antibiotic stewardship. Surveillance to antibiotic resistance is of importance to aid in planning and implementing infection prevention and control measures. The study was conducted to assess the resistance pattern to cefepime, clindamycin and meropenem, which are reserved antibiotics for use at tertiary hospitals in Tanzania. METHODS: A hospital-based antibiotic resistance surveillance was conducted between July and November 2019 at Muhimbili National Hospital and Bugando Medical Center, Tanzania. All organisms isolated were identified based on colony morphology, Gram staining and relevant biochemical tests. Antibiotic susceptibility testing was performed on Muller-Hinton agar using Kirby-Bauer disc diffusion method. Antibiotic susceptibility was performed according to the protocol by National Committee for Clinical Laboratory Standards. RESULTS: A total of 201 clinical samples were tested in this study. Urine (39.8%, n=80) and blood (35.3%, n=71) accounted for most of the collected samples followed by pus (16.9%, n=34). The bacterial resistance to clindamycin, cefepime and meropenem was 68.9%, 73.2% and 8.5%, respectively. About 68.4% Staphylococcus aureus isolates were resistant to clindamycin whereby 56.3%, 75.6%, 93.8% and 100% of the tested Escherichia coli, Klebsiella spp, Pseudomonas aeruginosa and Enterobacter cloacae, respectively, were cefepime resistant. About 8.5% of isolated Klebsiella spp were resistant and 6.4% had intermediate susceptibility to meropenem. Also, Pseudomonas aeruginosa was resistant by 31.2% and 25% had intermediate susceptibility to meropenem. CONCLUSION: The bacterial resistance to clindamycin and cefepime is high and low in meropenem. Henceforth, culture and susceptibility results should be used to guide the use of these antibiotics. Antibiotics with low resistance rate should be introduced to the reserve category and continuous antibiotic surveillance is warranted.

Bayesian Optimization of a Free-Electron Laser.

The Linac coherent light source x-ray free-electron laser is a complex scientific apparatus which changes configurations multiple times per day, necessitating fast tuning strategies to reduce setup time for successive experiments. To this end, we employ a Bayesian approach to maximizing x-ray laser pulse energy by controlling groups of quadrupole magnets. A Gaussian process model provides probabilistic predictions for the machine response with respect to control parameters, enabling a balance of exploration and exploitation in the search for the global optimum. We show that the model parameters can be learned from archived scans, and correlations between devices can be extracted from the beam transport. The result is a sample-efficient optimization routine, combining both historical data and knowledge of accelerator physics to significantly outperform existing optimizers.

Acute and chronic effects of multivitamin/mineral supplementation on objective and subjective energy measures.

BACKGROUND: Vitamins and minerals play an essential role within many cellular processes including energy production and metabolism. Previously, supplementation with a multivitamin/mineral (MVM) for ≥28 days resulted in improvements to cognition and subjective state. We have also demonstrated shifts in metabolism during cognitively demanding tasks following MVM in females, both acutely and following 8-week supplementation. The current study aimed to assess these effects further in males and females using metabolically challenging exercise and cognitive tasks. METHODS: The current randomised, placebo-controlled, parallel groups study investigated the effects of a MVM complex in 82 healthy young (18-35y) exercisers. Subjective ratings and substrate metabolism were assessed during 30 min each of increasingly effortful incremental exercise and demanding cognitive tasks. Assessments took place on acute study days following a single dose (Day 1) of MVM, containing 3 times recommended daily allowance of water-soluble vitamins plus CoQ10, and following 4-week supplementation (Day 28). RESULTS: Energy expenditure (EE) was increased during cognitive tasks following MVM across Day 1 and Day 28, with greater effects in males. In males, MVM also increased carbohydrate oxidation and energy expenditure during exercise across Day 1 and Day 28. In females, mental tiredness was lower during exercise; increases in physical tiredness following 30 min of exercise were attenuated; and stress ratings following cognitive tasks were reduced following MVM. In males, MVM only lowered mental tiredness following 10 min of exercise. These effects were apparent irrespective of day, but effects on mental tiredness were greater on Day 28. Ferritin levels were also higher on Day 28 in those receiving MVM. CONCLUSION: These findings extend on existing knowledge, demonstrating increased carbohydrate oxidation and increased energy expenditure in males following MVM supplementation for the first time. Importantly, they show modulation of energy expenditure and subjective tiredness following a single dose, providing further evidence for acute effects of MVM. Differential effects in men and women suggest that sex may play an important role in the effects of MVM on energy metabolism and should be considered in future research. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03003442. Registered 22nd November 2016 - retrospectively registered.